Nobel in physiology, medicine awarded to three Americans for discovery of 'clock genes'

Three Americans — Jeffrey C. Hall, Michael Rosbash and Michael W. Young — have won the 2017 Nobel Prize in physiology or medicine for their discoveries about the mechanisms that control an organism's circadian responses to light and dark.

Hall was born in New York, Rosbash in Kansas City, and they both worked at Brandeis University when they began their Nobel-winning work. Hall is now affiliated with the University of Maine. Michael Young was born in Miami and works at Rockefeller University.

In announcing the winner in Stockholm on Monday, the prize committee said the scientists elucidated how a life-form's “inner clock” can fluctuate to optimize our behavior and physiology. “Their discoveries explain how plants, animals and humans adapt their biological rhythm so that it is synchronized with the Earth's revolutions.”

Working with fruit flies, the scientists isolated a gene that is responsible for a protein that accumulates in the night but is degraded in the day. Misalignments in this clock may play a role in medical conditions and disorders, as well as the temporary disorientation of jet lag that travelers experience when crisscrossing time zones.

“The circadian system has its tentacles around everything,” Rosbash, a Howard Hughes Medical Institute investigator, explained in the HHMI Bulletin in 2014. “It’s ticking away in almost every tissue in the human body.” It's also in plants, including major food crops, the article noted, and appears to be tied to “disease susceptibility, growth rate, and fruit size.”

Young said that in the early days of their research many scientists thought of their work as a subset of neuroscience. They theorized that the brain may have a single, central clock controlling the cycles we've observed such as the rise and fall of our body temperature and blood pressure throughout the day. Now we know each living thing, including those without brains, may have many different clocks.

“We learned we are truly rhythmic organisms,” Young said in a phone interview. Today, “it’s hard to find a cell that does not oscillate in response to these clocks.”

From left to right, Michael Rosbash, Jeffrey C. Hall, and Michael W. Young. (AFP PHOTO/CHINESE UNIVERSITY OF HONG KONG)

The trio's early work took place in 1984 when Hall and Rosbash worked together at Brandeis and Young at Rockefeller University to isolate the “period” gene, which controls the circadian rhythm of fruit flies. Hall and Rosbash then showed that the level of the protein encoded by this gene changes in a 24-hour cycle, going up during the day and down at night. They theorized that this protein blocked the activity of the period gene.

But to have this effect, the protein would have to reach the genetic material in the cell nucleus, and no one was able to figure out how it got there until Young, in 1994, discovered a second clock gene, now known as “timeless.” He showed that when the protein encoded by timeless bound to the protein made by the gene period, they were able to enter the cell nucleus. He further identified a third gene, “doubletime,” which appeared to control the frequency of the oscillations over a 24-hour period.

Erin O’Shea, president of the Howard Hughes Medical Institute, said that people have observed for centuries that plants and animals change their behavior in sync with the light present in the natural environment. What Hall, Rosbash and Young figured out is how this happens.

“Genes make up the mechanics by which organisms can keep track of time and this allows them — just like your wristwatch — to coordinate their behavior their sleep-wake cycle with the changes in the light-dark cycle,” she said.

The circadian clock anticipates and adapts our physiology to the different phases of the day. (The Nobel Assembly at Karolinska Institutet)

Researchers in the field of circadian biology — or “chronobiology,” as it is nicknamed — said Monday that the scientists’ work has had a major influence on their work in human health and medicine. Alzheimer’s, depression, attention-deficit/hyperactivity disorder (ADHD), heart disease, obesity and diabetes and other metabolic issues are among the many conditions that appear to be linked to circadian rhythms being out of whack.

Erol Fikrig, a researcher at Yale University who is studying whether the timing of insect bites impacts our ability to fight off diseases like dengue fever or Lyme disease, explained that our immune system, too, “is influenced by circadian rhythm, which can alter our ability to fight infections.”

Amita Sehgal, a neuroscientist at the University of Pennsylvania, was a postdoctoral student in Young’s lab from 1988 to 1993 and worked on the clock genes. Her research these days involves looking at how sleep appears to be controlled by the circadian clock. Although we sleep at night, our need to sleep appears to be independent of the clock. “If you didn't have a clock, you would still sleep, but it would be randomly distributed throughout the day,” she said.

Young said that one of the most important areas of study built on their work is what happens when the clock runs too fast or too slow. Most recently, scientists have discovered that one percent of humans worldwide have a mutation in the clock genes that is associated with delayed sleep or being a night owl. He said many of these individuals show up at sleep clinics wondering what to do, and the work provides a target to work on.

“That’s powerful information that can inform lots of future work in the development of therapies,” he said.

Young said there's also growing research — mostly in animals — that supports the idea that maintaining a more regular schedule, including eating and sleeping, may contribute to longevity.

“This may be back to going back to what people used to do before they had refrigerators and electric lights,” he said.

This year's winners probably weren't in a lot of Nobel Prize betting pools, because the medicine Nobel is notoriously hard to predict. In fact, during a news conference at which the awards were announced, a member of the Nobel Assembly at Karolinska Institutet said that when he informed Rosbash that he had received the award, his response was, “You are kidding me.”

The highly secretive Nobel committee does not release a list those under consideration for its awards and never has in its 116-year history. The names being thrown around as deserving of the prize in the weeks before the announcement is always very long and highly speculative. David Pendlebury, formerly of Thomson Reuters and now with Clarivate Analytics, bases his picks on an extensive data analysis and has an impressive track record of correctly picking numerous Nobel Laureates over the past 15 years (although not always in the right year).

This year, he identified as possible winners Yuan Chang and Patrick Moore of the University of Pittsburgh for their work with human herpesvirus 8 (KSHV/HHV8) which is associated with cancer; Lewis Cantley of Weill Cornell of Medicine for the discovery of a cell signaling pathway and its role in tumor growth; and Karl J. Friston of the University College London for his work on algorithms and techniques for the analysis of brain imaging data. Perhaps one of those picks will win next year.

In recent years, the Nobel in medicine has been awarded for breakthroughs in a wide range of work in human biology: a Japanese scientist who discovered a key mechanism in our body’s defense system that involves recycling parts of cells and plays an important role in cancer; a trio who worked on treatments for river blindness and malaria; and researchers who deciphered the brain's “GPS” that allows us to orient ourselves in space.

The Nobel Prize in physics will be announced on Tuesday, the chemistry award on Wednesday, literature on Thursday and the peace prize on Friday. An award in economics in memory of Alfred Nobel (which is not one of the original Nobel Prizes) will be announced Monday.

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